Over the last decade, major advances have been made in the understanding of the biology of the mammalian tachykinin neuropeptides. It is now well established that substance-P (1), neurokinin A (NKA) (2), and neurokinin B (NKB) (3), all of which share a common C-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2, (Nakanishi S., Physiol. Rev., 67:117 (1987)), are widely distributed throughout the periphery and central nervous system (CNS) where they appear to interact with at least three receptor types referred to as NK.sub.1, NK.sub.2, and NK.sub.3, (Guard S., et al., Neurosci. Int., 18:149 (1991)). Substance-P displays highest affinity for NK.sub.1 receptors, whereas NKA and NKB bind preferentially to NK.sub.2 and NK.sub.3 receptors, respectively. Recently, all three receptors have been cloned and sequenced and shown to be members of the G-protein-linked "super family" of receptors (Nakanishi S., Annu. Rev. Neurosci., 14:123 (1991)). A wealth of evidence supports the involvement of tachykinin neuropeptides in a variety of biological activities including pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system (inflammatory pain), and neurogenic inflammation (Pernow B., Pharmacol. Rev., 35:85 (1983)). However, to date, a detailed understanding of the physiological roles of tachykinin neuropeptides has been severely hampered by a lack of selective, high affinity, metabolically stable tachykinin receptor antagonists that possess both good bioavailability and CNS penetration. Although several tachykinin receptor antagonists have been described (Tomczuk B. E., et al., Current Opinions in Therapeutic Patents, 1:197 (1991)), most have been developed through the modification and/or deletion of one or more of the amino acids that comprise the endogenous mammalian tachykinins such that the resulting molecules are still peptides that possess poor pharmacokinetic properties and limited in vivo activities.
However, since 1991, a number of high-affinity nonpeptide antagonists have been reported. Snider R. M., et al., (Science, 251:435 (1991)), and Garret C., et al., (Proc. Natl. Acad. Sci., 88.:10208 (1991)), described CP-96,345 and RP 67580, respectively, as antagonists at the NK.sub.1 receptor, while Advenier C., et al., (Brit. J. Pharmacol., 105:78 (1992)), presented data on SR 48968 showing its high affinity and selectivity for NK.sub.2 receptors. More recently Macleod, et al., (J. Med. Chem., 36:2044 (1993)) have published on a novel series of tryptophan derivatives as NK.sub.1 receptor antagonists. It is of interest that most of the nonpeptide tachykinin receptor antagonists described to date arose, either directly or indirectly, out of the screening of large compound collections using a robust radioligand binding assay as the primary screen. Recently, FK 888, a "dipeptide" with high affinity for the NK.sub.1 receptor was described (Fujii J., et al., Neuropeptide, 22:24 (1992)). Only one NK.sub.3 receptor selective ligand, SR 142801, has been published on to date (Edmonds-Alt, et al., Life Sciences, 56:27 (1995)).
International Publication Numbers WO 93/01169, WO 93/01165, and WO 93/001160 cover certain nonpeptide tachykinin receptor antagonists.
NKB and also NK.sub.3 receptors are distributed throughout the periphery and central nervous system (Maggi, et al., J. Auton. Pharmacol., 13:23 (1993)). NKB is believed to mediate a variety of biological actions via the NK.sub.3 receptor including gastric acid secretion; appetite regulation; modulation of serotonergic, cholinergic, and dopaminergic systems; smooth muscle contraction and neuronal excitation. Recent publications descriptive of this art include Polidor, et al., Neuroscience Letts., 103:320 (1989); Massi, et al., Neuroscience Letts., 92:341 (1988), and Improta, et al., Peptides, 12:1433 (1991). Due to its actions with dopaminergic (Elliott, et al., Neuropeptides, 19:119 (1991)), cholinergic (Stoessl, et al., Psycho. Pharmacol., 95:502 (1988)), and serotonergic (Stoessl, et al., Neuroscience Letts., 80:321 (1987)) systems, NKB may play a role in psychotic behavior, memory functions, and depression.
Accordingly, compounds capable of antagonizing the effects of NKB at NK.sub.3 receptors will be useful in treating or preventing a variety of disorders including pain, depression, anxiety, panic, schizophrenia, neuralgia, addiction disorders, inflammatory diseases; gastrointestinal disorders including colitis, Crohn's disease, inflammatory bowel disorder, and satiety; vascular disorders such as angina and migraine and neuropathological disorders such as Parkinsonism and Alzheimer's.
Co-pending application Ser. No. 08/346,052 filed Nov. 29, 1994, covers certain peptides of Formula I ##STR1## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is hydrogen,
OR.sup.4, PA2 CO.sub.2 R.sup.4, PA2 cyclo- or polycycloalkyl of from 4 to 10 carbons with from 0 to 3 substituents selected from: PA2 phenyl unsubstituted or substituted by from 1 to 3 groups selected from: PA2 alkyl, PA2 halogen, PA2 nitro, PA2 CF.sub.3, PA2 (CH.sub.2).sub.t OR.sup.6, PA2 (CH.sub.2).sub.t CO.sub.2 R.sup.6, or PA2 (CH.sub.2).sub.t NR.sup.6 R.sup.7 wherein t is an integer of from 0 to 6 and R.sup.6 and R.sup.7 are each independently hydrogen or alkyl; PA2 --CONH--, PA2 --CONCH.sub.3 --, PA2 --COO--, PA2 --CH.sub.2 NH--, PA2 --NHCO--, PA2 --CH.sub.2 O--, PA2 --COCH.sub.2 --, or PA2 --CH.sub.2 CH--; PA2 straight or branched alkyl of from 3 to 10 carbons with from 0 to 3 substituents selected from: PA2 alkyl, PA2 halogen, PA2 nitro, PA2 trifluoromethyl, PA2 cyano, PA2 hydroxy, and PA2 alkoxy; PA2 pyridine, PA2 thiophene, PA2 naphthyl, PA2 indole, PA2 benzofuran, PA2 benzothiophene, or PA2 imidazole; PA2 --OCONH--, PA2 --CONH--, PA2 --CO.sub.2 --, PA2 --NHCONH--, PA2 --CH.sub.2 NH--, PA2 --COCH.sub.2 --, PA2 --CONCH.sub.3 --, PA2 --CH.sub.2 O--, PA2 --CH.sub.2 CH.sub.2 --, or PA2 --CH.dbd.CH--; PA2 hydrogen, PA2 methyl, PA2 phenyl, PA2 benzyl, PA2 CH.sub.2 C.sub.6 H.sub.11, or ##STR4## R.sup.3 is hydrogen or methyl; Y is PA2 --(CH.sub.2).sub.m --, PA2 --(CH.sub.2).sub.m O--, wherein m is an integer of from 1 to 5, PA2 --CONH--, PA2 --CH.sub.2 NH--, PA2 --COCH.sub.2 --, or PA2 --CH.dbd.CH--; and PA2 hydrogen, PA2 OR.sup.5, PA2 NHCOCH.sub.3, PA2 NR.sup.5 R.sup.6, PA2 SO.sub.2 CH.sub.3, PA2 SO.sub.2 NH.sub.2, PA2 NHSO.sub.2 NH.sub.2, PA2 NHCONH.sub.2, PA2 CONR.sup.5 R.sup.6, PA2 COR.sup.5, ##STR5## wherein R.sup.5 and R.sup.6 are each independently hydrogen or alkyl, and R.sup.4 is ##STR6## wherein p is an integer of from 0 to 5, q is an integer of from 0 to 4, and R.sup.7 is hydrogen, hydroxy, alkoxy, CONR.sup.5 R.sup.6, or NHCONR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are as described above. PA2 alkyl, PA2 halogen, PA2 cyano, and PA2 alkoxy; PA2 pyridine, PA2 thiophene, PA2 naphthyl, or PA2 benzofuran; PA2 OCONH, PA2 CONH, PA2 NHCONH, PA2 CH.sub.2 NH, PA2 CONCH.sub.3, or PA2 COCH.sub.2 ; PA2 hydrogen, PA2 phenyl, PA2 benzyl, or ##STR7## R.sup.3 is hydrogen or methyl; Y is (CH.sub.2).sub.m, CONH, CH.sub.2 NH, or COCH.sub.2 ; PA2 OR.sup.5, PA2 NHCOCH.sub.3, PA2 SO.sub.2 CH.sub.3, PA2 SO.sub.2 NH.sub.2, PA2 NHSO.sub.2 NH.sub.2, PA2 NHCONH.sub.2, PA2 CONR.sup.5 R.sup.6, PA2 COR.sup.5 PA2 hydroxy, PA2 NHCOCH.sub.3, PA2 NHCONH.sub.2.
alkyl, PA3 halogen, PA3 (CH.sub.2).sub.m CO.sub.2 R.sup.4, PA3 (CH.sub.2).sub.m OR.sup.4 wherein m is an integer of from 1 to 6 and R.sup.4 is hydrogen or alkyl, or PA3 alkyl, PA3 halogen, PA3 nitro, PA3 CF.sub.3, PA3 (CH.sub.2).sub.p OR.sup.6, PA3 (CH.sub.2).sub.p CO.sub.2 R.sup.6, PA3 (CH.sub.2).sub.p NR.sup.6 R.sup.7 wherein p is an integer of from 0 to 6 and R.sup.6 and R.sup.7 are each independently hydrogen or alkyl; PA3 (CH.sub.2).sub.n OR.sup.8, PA3 CO.sub.2 R.sup.8, PA3 --NHCOCH.sub.3, PA3 --NR.sup.8 R.sup.9, PA3 --SO.sub.2 Me, PA3 --SOMe, PA3 --SO.sub.2 NH.sub.2, PA3 --CONR.sup.8 R.sup.9, PA3 --NHCONR.sup.8 R.sup.9, PA3 --COR.sup.4 wherein n is an integer of from 0 to 6, R.sup.4 is as above, R.sup.8 and R.sup.9 are each independently hydrogen or alkyl, PA3 --guanidine, PA3 --amidine;
A is --(CH.sub.2).sub.q (C(CH.sub.3).sub.2).sub.r (CH.sub.2).sub.s -- wherein q, r, and s are integers of from 0 to 6, 0 to 1, and 0 to 6, respectively; PA1 Ar.sup.1 and Ar.sup.2 are each independently phenyl unsubstituted or substituted with from 1 to 3 substituents selected from: PA1 X and Y are each independently PA1 n is an integer of from 0 to 10; and PA1 R.sup.3 is hydrogen, PA1 R.sup.3 is also ##STR2## wherein t is an integer of from 0 to 5, v is an integer of from 0 to 2, u is an integer of from 0 to 4, and R.sup.10 is hydrogen, hydroxy, alkoxy, COOH, CO.sub.2 alkyl, CONR.sup.8 R.sup.9, NMCONR.sup.8 R.sup.9 guanidine or amidine; and PA1 the .circle-solid., .tangle-solidup., and .box-solid. indicate all stereoisomers at these carbon atoms; PA1 Ar.sup.1 is phenyl unsubstituted or substituted by from 1 to 3 substituents selected from: PA1 Ar.sup.1 can also be pyridine; PA1 R.sup.1 is hydrogen or a straight, branched, or cycloalkyl of from 1 to 7 atoms; or PA1 Ar.sup.1 and R.sup.1 form a ring of 5 to 8 atoms when joined by a bond; PA1 n is an integer of from 0 to 2; PA1 A is OCONH, CONH, CO.sub.2, NHCONH, CH.sub.2 NH, and COCH.sub.2 ; PA1 Ar.sup.2 is phenyl as defined in Ar.sup.1 above: PA1 X is PA1 R.sup.2 is PA1 R.sup.4 is hydrogen, alkyl straight or branched of from 1 to 8 atoms unsubstituted or substituted by a substituent selected from: PA1 .circle-solid. is S or R, .tangle-solidup. is R, and .tangle-solidup. is S; Ar.sup.1 is phenyl unsubstituted or substituted with from 1 to 2 substituents selected from: PA1 R.sup.1 is a straight, branched, or cyclic alkyl of from 1 to 6 atoms; or PA1 Ar.sup.1 and R.sup.1 form a ring of 7 atoms; PA1 n is an integer of from 0 to 1; PA1 A is OCONH, CONH, NHCONH, or CH.sub.2 NH; PA1 A.sup.2 is phenyl as defined in Ar.sup.1 above, PA1 X is PA1 R.sup.2 is PA1 R.sup.4 is hydrogen, alkyl straight or branched of from 3 to 7 atoms with a substituent selected from: PA1 wherein R.sup.5 and R.sup.6 are each independently hydrogen or alkyl, and PA1 R.sup.4 is ##STR8## wherein p is an integer of from 0 to 2, q is an integer of from 0 to 3, and R.sup.7 is hydroxy, alkoxy, CONR.sup.5 R.sup.6, or NHCONR.sup.5 R.sup.6. PA1 .circle-solid. is S or R, .tangle-solidup. is R, and .box-solid. is S; PA1 Ar.sup.1 is phenyl unsubstituted or substituted by halogen, cyano, or alkyl; PA1 R.sup.1 is a branched or cycloalkyl of from 3 to 6 carbon atoms, or Ar.sup.1 and R.sup.1 are joined to form a ring of 7 atoms; PA1 n is zero; PA1 A is OCONH or NHCONH; PA1 Ar.sup.2 is phenyl unsubstituted or substituted by halogen, cyano or alkyl, or PA1 Ar.sup.2 is thiophene, naphthyl, or benzofuran; PA1 X is CONH, CH.sub.2 NH, or COCH.sub.2 ; PA1 R.sup.2 is hydrogen, phenyl or ##STR9## R.sup.3 is hydrogen or methyl; Y is CH.sub.2 or CONH; PA1 R.sup.4 is hydrogen, alkyl which is a straight chain of from 4 to 6 atoms with a substituent selected from:
.circle-solid. and .tangle-solidup. indicate all stereoisomers.
Copending application Ser. No. 08/344,064 covers certain tachykinin antagonists. It is hereby incorporated by reference.
The compounds of the instant invention provide small molecules which are not peptides; they are monoamino acids in contrast to the dipeptides of the co-pending application. The instant compounds have only one amide linkage and show superior binding affinities.